Associations between psychophysiological, immune, endocrine, and serotonergic biomarkers of stress and gastrointestinal symptoms in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is often accompanied by gastrointestinal (GI) disturbances, which also may impact behavior. Alterations in autonomic, endocrine, and immune system functioning are also frequently observed in ASD, however, the relationship between these findings in ASD is not known. To study this relationship, an initial pilot study was conducted in our lab which revealed increased autonomic nervous system (ANS) functioning in response to brief stress-invoking peripheral stimuli and GI disorders in ASD. Preliminary data suggested an enhanced stress response in individuals with ASD and co-occurring GI disorders. In a subsequent multi-site study, we examined the relationship between GI symptomatology, examining upper and lower GI tract symptomatology separately, ANS functioning, and salivary cortisol at baseline and in response to stress in a sample of 120 children with ASD. The stress-associated proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-[alpha]) and whole blood serotonin concentrations were also assessed. While the number of participants with significant upper GI tract problems was small in this sample, 42.5% of participants met criteria for functional constipation, a disorder of the lower GI tract. Heart rate variability, a measure of parasympathetic modulation of cardiac activity, was found to be positively associated with lower GI tract symptomatology at baseline. This relationship was particularly strong for participants with co-occurring diagnoses of anxiety disorder and for those with a history of regressive ASD or loss of previously acquired skills. A greater amount of lower GI tract symptoms was significantly associated with post-stress cortisol concentration, and this relationship was greatest for individuals with regressive ASD. However, symptoms of the lower GI tract were not associated with the stress-responsive cytokines IL-6 and TNF-[alpha]. Finally, in a sample of 82 of the 120 children mentioned above, a significant positive correlation was found between lower GI tract symptoms and whole-blood serotonin. These findings suggest that systems involved in the response to mild stimuli are different in individuals with ASD and co-occurring GI issues, especially for constipation; although it is not possible to assess causality in this data set. Future work should examine the impact of treatment of GI problems on autonomic function and anxiety, as well as the impact of anxiety treatment on GI problems. Thus, clinicians should be aware that GI problems, anxiety, autonomic, endocrine, and immune dysfunction may cluster in children with ASD and should be addressed in a multidisciplinary treatment plan.